CLINICAL EVIDENCE CONCISE: A PUBLICATION OF BMJ PUBLISHING GROUP

Thromboembolism

DAVID A. FITZMAURICE, M.D., F.D. RICHARD HOBBS, and RICHARD J. MCMANUS, M.SC., The Medical School University of Birmingham, Birmingham, United Kingdom

Am Fam Physician. 2004 Jan 1;69(1):132-134.

What are the effects of treatments for proximal deep venous thrombosis?

TRADE OFF BETWEEN BENEFITS AND HARMS

Unfractionated and Low-Molecular-Weight Heparin

Systematic reviews have found that low-molecular-weight heparin (LMWH) reduces the incidence of recurrent thromboembolic disease and decreases the risk of major hemorrhage compared with unfractionated heparin. One systematic review found no significant difference between long-term LMWH and oral anticoagulation in recurrent thromboembolism, major hemorrhage, or mortality. One systematic review of randomized controlled trials (RCTs) found no significant difference in recurrence of thromboembolism between heparin treatment at home and in the hospital.

Warfarin

We found no RCTs comparing warfarin versus placebo. One RCT found that fewer people had recurrence of proximal deep venous thrombosis (DVT) within six months with combined acenocoumarol (nicoumalone) plus intravenous unfractionated heparin than with acenocoumarol alone; as a result, the trial was stopped. Systematic reviews have found that longer duration of anticoagulation reduces recurrence of DVT compared with shorter duration of anticoagulation. One non-systematic review found limited evidence that longer duration compared with shorter duration of warfarin was associated with an increased risk of major hemorrhage, but another nonsystematic review found no significant difference in major hemorrhage. The absolute risk of recurrent venous thromboembolism decreases with time, but the relative risk reduction with treatment remains constant. Harms of treatment, including major hemorrhage, continue during prolonged treatment. Individuals have different risk profiles, and it is likely that the optimal duration of anticoagulation will vary.

UNKNOWN EFFECTIVENESS

Compression Stockings

We found no RCTs of standard compression stockings in the treatment of people with proximal DVT. One RCT found that made-to-measure, knee-length, graduated compression stockings reduced post-thrombotic syndrome over five to eight years compared with no stockings.

What are the effects of treatments for isolated calf venous thrombosis?

TRADE OFF BETWEEN BENEFITS AND HARMS

Warfarin Plus Heparin

One unblinded RCT found no significant difference in recurrent thromboembolism or rates of major hemorrhage between six and 12 weeks of anticoagulation. One RCT found that warfarin plus intravenous unfractionated heparin (international normalized ratio: > 2.5 to 4.2) reduced the rate of proximal extension compared with heparin alone.

What are the effects of treatments for pulmonary embolism?

TRADE OFF BETWEEN BENEFITS AND HARMS

Oral Anticoagulants

We found no direct evidence about the optimal intensity and duration of anticoagulation in people with pulmonary embolism. The best available evidence requires extrapolation of results from studies of people with proximal DVT.

Unfractionated and Low-Molecular-Weight Heparin

One small RCT in people with pulmonary embolism found that heparin plus warfarin reduced mortality compared with no anticoagulation at one year. One RCT in people with symptomatic pulmonary embolism who did not receive thrombolysis or embolectomy found no significant difference between LMWH and unfractionated heparin in mortality or new episodes of thromboembolism. Another RCT in people with proximal DVT without clinical signs or symptoms of pulmonary embolism but with high probability lung scan findings found that fixed-dose LMWH reduced the proportion of people with new episodes of venous thromboembolism compared with intravenous heparin.

UNLIKELY TO BE BENEFICIAL

Thrombolysis

RCTs identified by one systematic review found no significant difference in mortality between thrombolysis plus heparin and heparin alone, and found that thrombolysis may increase the incidence of intracranial hemorrhage. One small RCT identified by the review found limited evidence that adding thrombolysis to heparin may reduce mortality in people with shock caused by massive pulmonary embolism.

What are the effects of computerized decision support on oral anticoagulation management?

UNKNOWN EFFECTIVENESS

Computerized Decision Support in Oral Anticoagulation Management

We found no RCTs comparing computerized decision support versus usual management of oral anticoagulation that used clinically important outcomes (major hemorrhage or death).

One systematic review and three subsequent RCTs have found that, compared with usual care, computerized decision support in oral anticoagulation increases time spent in the target international normalized ratio range. Another subsequent RCT found no significant difference between computerized decision support and standard manual support in the time spent in the target international normalized ratio range. A subsequent RCT of initiation of warfarin found that computerized decision support reduced the mean time taken to reach therapeutic levels of anticoagulation compared with usual care. Most RCTs were small and brief.

Definitions

Venous thromboembolism is any thromboembolic event occurring within the venous system, including DVT and pulmonary embolism. DVT is a radiologically confirmed partial or total thrombotic occlusion of the deep venous system of the legs sufficient to produce symptoms of pain or swelling. Proximal DVT affects the veins above the knee (i.e., popliteal, superficial femoral, common femoral, and iliac veins). Isolated calf venous thrombosis is confined to the deep veins of the calf and does not affect the veins above the knee. Pulmonary embolism is radiologically confirmed partial or total thromboembolic occlusion of pulmonary arteries, sufficient to cause symptoms of breathlessness, chest pain, or both. Post-thrombotic syndrome is edema, ulceration, and impaired viability of the subcutaneous tissues of the leg occurring after DVT. Recurrence refers to symptomatic deterioration because of a further (radiologically confirmed) thrombosis, after a previously confirmed thromboembolic event, where there had been an initial, partial, or total symptomatic improvement. Extension refers to a radiologically confirmed new, constant, symptomatic intraluminal filling defect extending from an existing thrombosis.

Incidence/Prevalence

We found no reliable study of the incidence/prevalence of DVT or pulmonary embolism in the United Kingdom. A prospective Scandinavian study found an annual incidence of 1.6 to 1.8 per 1,000 people in the general population.1,2 One postmortem study estimated that 600,000 people develop pulmonary embolism each year in the United States, of whom 60,000 die as a result.3

Etiology/Risk Factors

Risk factors for DVT include immobility, surgery (particularly orthopedic), malignancy, smoking, pregnancy, older age, and inherited or acquired prothrombotic clotting disorders.4 The oral contraceptive pill is associated with death caused by venous thromboembolism (absolute risk increases with any combined oral contraception: 1 to 3 per million women a year).5 The principal cause of pulmonary embolism is a DVT.4

Prognosis

The annual recurrence rate of symptomatic calf venous thrombosis in people without recent surgery is greater than 25 percent.6,7 Proximal extension develops in 40 to 50 percent of people with symptomatic calf venous thrombosis.8 Proximal DVT may cause fatal or nonfatal pulmonary embolism, recurrent venous thrombosis, and the post-thrombotic syndrome. One case series (462 people) published in 1946 found 5.8 percent mortality from pulmonary emboli in people in the hospital with untreated DVT.9 One nonsystematic review of observational studies found that, in people after recent surgery who have an asymptomatic deep calf venous thrombosis, the rate of fatal pulmonary embolism was 13 to 15 percent.10 The incidence of other complications without treatment is not known. The risk of recurrent venous thrombosis and complications is increased by thrombotic risk factors.11

Richard Hobbs has received travel sponsorship and honoraria from several multinational biotechnology and pharmaceutical companies with cardiovascular products for plenary talks and attendance at major cardiology scientific congresses and conferences.

David Fitzmaurice has been reimbursed by LEO Laboratories for speaking at and attending symposia